US20120220600A1 - N-Oxide of 3-(2,6-dichloro-3,5-dimethoxy-phenyl) -1--1-methyl-urea - Google Patents
N-Oxide of 3-(2,6-dichloro-3,5-dimethoxy-phenyl) -1--1-methyl-urea Download PDFInfo
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- US20120220600A1 US20120220600A1 US13/504,258 US201013504258A US2012220600A1 US 20120220600 A1 US20120220600 A1 US 20120220600A1 US 201013504258 A US201013504258 A US 201013504258A US 2012220600 A1 US2012220600 A1 US 2012220600A1
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- compound
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- pharmaceutically acceptable
- disease
- protein kinase
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- QADPYRIHXKWUSV-UHFFFAOYSA-N CCN1CCN(C2=CC=C(NC3=NC=NC(N(C)C(=O)NC4=C(Cl)C(OC)=CC(OC)=C4Cl)=C3)C=C2)CC1 Chemical compound CCN1CCN(C2=CC=C(NC3=NC=NC(N(C)C(=O)NC4=C(Cl)C(OC)=CC(OC)=C4Cl)=C3)C=C2)CC1 QADPYRIHXKWUSV-UHFFFAOYSA-N 0.000 description 4
- IDSSMACKJBFYFA-UHFFFAOYSA-N CCN1(O)CCN(C2=CC=C(NC3=NC=NC(N(C)C(=O)NC4=C(Cl)C(OC)=CC(OC)=C4Cl)=C3)C=C2)CC1 Chemical compound CCN1(O)CCN(C2=CC=C(NC3=NC=NC(N(C)C(=O)NC4=C(Cl)C(OC)=CC(OC)=C4Cl)=C3)C=C2)CC1 IDSSMACKJBFYFA-UHFFFAOYSA-N 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- the compound of Formula I is a protein kinase inhibitor and is useful in the treatment of proliferative diseases mediated by protein kinases.
- the compound of Formula I inhibits fibroblast growth factor receptor (FGFR) tyrosine kinases. It is therefore useful in the treatment of certain cancers in which FGFR kinases are implicated including breast cancer, gastric cancer, lung cancer, cancer of the prostate, bladder cancer and endometrial cancer.
- FGFR fibroblast growth factor receptor
- an N-oxide of 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl ⁇ -1-methyl-urea which may be prepared, for example, by oxidizing 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)phenylamino]-pyrimidin-4-yl ⁇ -1-methyl-urea with an oxidizing agent, such as, mCPBA), compositions including the compound, and methods of preparing the compound and compositions.
- an oxidizing agent such as, mCPBA
- the present technology further provides methods of using the compound and compositions of the present technology to treat various diseases, alone and in combination with other suitable agents, including but not limited to, those that can be prevented, inhibited or ameliorated by inhibition of kinase activity selected from fibroblast growth factor receptor 1 (FGFR1), fibroblast growth factor receptor 2 (FGFR2), fibroblast growth factor receptor 3 (FGFR3), and fibroblast growth factor receptor 4 (FGFR4).
- suitable agents including but not limited to, those that can be prevented, inhibited or ameliorated by inhibition of kinase activity selected from fibroblast growth factor receptor 1 (FGFR1), fibroblast growth factor receptor 2 (FGFR2), fibroblast growth factor receptor 3 (FGFR3), and fibroblast growth factor receptor 4 (FGFR4).
- FGFR1 fibroblast growth factor receptor 1
- FGFR2 fibroblast growth factor receptor 2
- FGFR3 fibroblast growth factor receptor 3
- FGFR4 fibroblast growth factor receptor 4
- the compound of formula I may have lower cardiovascular toxicity than the non-oxidized form from which it is derived (i.e., 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl ⁇ -1-methyl-urea) while retaining beneficial biological activity.
- the pharmaceutically acceptable salts are those formed from salt-forming groups having basic or acidic properties.
- Compounds having at least one basic group or at least one basic radical, for example amino, a secondary amino group or a pyridyl radical may form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulfuric acid or a phosphoric acid, or with suitable organic carboxylic, sulfonic, or other organic acids, for example aliphatic mono- or di-carboxylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid or oxalic acid, or amino acids such as arginine or lysine, aromatic carboxylic acids, such as benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid, or 4-aminosalicylic
- the oxidizing agent is a peroxide, a peracid, or dimethyldioxirane (Me 2 CO 2 ).
- the compound produced is a mono-N-oxide, and in others a mixture of N-oxides is produced.
- the process further comprises separating the mono-N-oxide from bis-N-oxides and/or other oxides. A variety of methods may be used for the separating, including, without limitation, column chromatography.
- peroxides refer to compounds which include a hydroperoxy (—OOH) moiety and which are not peracids.
- peroxides include, without limitation, hydrogen peroxide and urea-hydrogen peroxide, and alkyl hydroperoxides such as tertiary butyl hydroperoxide.
- peracids refer to acids in which the OH moiety of a carboxyl group or an inorganic oxyacid, is replaced by an OOH moiety.
- percarboxylic acids include, without limitation, performic acid and peracetic acid.
- the peracid is meta chloroperbenzoic acid (mCPBA).
- mCPBA meta chloroperbenzoic acid
- An example of an inorganic peracid is oxone, which is a salt of persulfuric acid (i.e., a persulfate).
- Salts, particularly acid salts, of the compound of formula II are also useful for producing the compounds of the present technology according to the processes disclosed herein.
- Acid salts useful for this purpose can be prepared from acids as described above, and may be, but need not be, pharmaceutically acceptable acid salts.
- the salt of the compound of formula II is a pharmaceutically acceptable salt.
- the product produced by the process is a pharmaceutically acceptable salt.
- the present technology provides a method of preparing the N-oxide of the present technology comprising contacting a compound of formula II (as shown above) or a salt thereof with an oxidizing agent to provide the compounds of the present technology, including the compound of formula I or salts thereof or pharmaceutically acceptable salts thereof.
- the oxidizing agent is a peroxide or a peracid.
- a variety or peroxides and peracids, including percarboxylic acids and inorganic peracids, as described above, are useful in the methods of the present technology.
- the oxidizing agent is meta chloroperbenzoic acid (mCPBA).
- the method is performed in a solvent.
- the solvent contains an acid, such as, and without limitation, acetic acid.
- the reaction is performed using reactants (the compound of formula II and the oxidizing agent) and one or more solvents that are substantially free of water.
- Salts, particularly acid salts, of the compound of formula II are also useful according to the methods of the present technology.
- Acid salts useful for this purpose can be prepared from acids described above, and additionally, need not be pharmaceutically acceptable acid salts.
- the oxidizing agent contacted is present in an amount from about 1 equivalent to about 5 equivalents, about 2 equivalents to about 4 equivalents, and about 3 equivalents, with respect to the molar amount of the compound of formula II or an acid salt of the compound of formula II.
- the reactants are reacted or contacted from about 0.3 h to about 3 h, from about 0.6 h to about 2 h, or about 1 h.
- the reactants are reacted at a temperature in the range of about ⁇ 5° C. to about 15° C., about 0° C. to about 10° C., or about 5° C.
- the present technology provides compositions comprising the compound, or a pharmaceutically acceptable salt thereof, of the present technology, and a pharmaceutically acceptable carrier, excipient, or diluent.
- the compositions are pharmaceutical compositions.
- the compounds of the present technology may be used, for example, for the preparation of pharmaceutical compositions that comprise a therapeutically effective amount of a compound of the present technology or a pharmaceutically acceptable salt thereof, as active ingredient together or in admixture with a significant amount of one or more inorganic or organic, solid or liquid, pharmaceutically acceptable carriers, excipients, and/or diluents.
- a “therapeutically effective amount” refers to an amount of the compound, a pharmaceutically acceptable salt thereof, or compositions including them, that alleviates or ameliorates, in whole or in part, symptoms associated with the disorder or disease treated, or slows or halts of further progression or worsening of its symptoms, or prevents or provides prophylaxis for the disease or disorder in a subject at risk for developing the disease or disorder.
- a “subject” is any warm blooded animal that can benefit from the administration of the compound, a pharmaceutically acceptable salt thereof, or compositions including them, as disclosed herein.
- the subject is a mammal, for example, a human, a primate, a dog, a cat, a horse, a cow, a pig, a rodent, such as for example a rat or mouse.
- the mammal is a human.
- the protein kinase is a tyrosine kinase.
- the protein kinase is FGFR1, FGFR2, FGFR3, or FGFR4.
- compositions for enteral administration such as nasal, buccal, rectal or, especially, oral administration, and for parenteral administration, such as intravenous, intramuscular or subcutaneous administration, to a subject, especially humans, are provided in accordance with the present technology.
- the compositions comprise the active ingredient alone or, together with a pharmaceutically acceptable carrier.
- the dosage of the active ingredient depends upon the disease to be treated and upon the species, its age, weight, and individual condition, the individual pharmacokinetic data, and the mode of administration.
- the technology relates also to pharmaceutical compositions for use in a method for the prophylactic or, especially, therapeutic management of the human or animal body, to a process for the preparation thereof (especially in the form of compositions for the treatment of tumors) and to a method of treating tumor diseases, especially those tumor diseases, which can be prevented, inhibited or ameliorated by inhibition of the activity of a protein kinase described above.
- the pharmaceutical compositions comprise from approximately 1% to approximately 95% active ingredient, single-dose administration forms comprising in certain embodiment from approximately 20% to approximately 90% active ingredient and forms that are not of single-dose type comprising in certain embodiment from approximately 5% to approximately 20% active ingredient.
- Unit dose forms are, for example, coated and uncoated tablets, ampoules, vials, suppositories, or capsules.
- Further dosage forms are, for example, ointments, creams, pastes, foams, tinctures, sprays, etc. Examples are capsules containing from about 0.05 g to about 1.0 g active ingredient.
- compositions of the present technology are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.
- solutions of the active ingredient are used, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions which, for example in the case of lyophilized compositions comprising the active ingredient alone or together with a carrier can be made up before use.
- the pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving and lyophilizing processes.
- Such solutions or suspensions may comprise viscosity-increasing agents or solubilizers, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinyl pyrrolidone or gelatin.
- Suspensions in oil comprise as the oil component the vegetable, synthetic or semi-synthetic oils customary for injection purposes.
- liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brasidic acid or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, ⁇ -carotene or 3,5-di-tert-butyl-4-hydroxytoluene.
- the alcohol component of those fatty acid esters has a maximum of 6 carbon atoms and is a mono- or poly-hydroxy, for example a mono-, di- or tri-hydroxy, alcohol, for example methanol, ethanol, propanol, butanol or pentanol or the isomers thereof, but especially glycol and glycerol.
- fatty acid esters are therefore to be mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, “Labrafil M 2375” (polyoxyethylene glycerol trioleate, Gattefossé, Paris), “Miglyol 812” (triglyceride of saturated fatty acids with a chain length of C 8 to C 12 , Hüls AG, Germany), but especially vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and more especially groundnut oil.
- vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and more especially groundnut oil.
- Injection compositions are prepared in customary manner under sterile conditions; the same applies also to introducing the compositions into ampoules or vials and sealing the containers.
- compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture, if desired or necessary, after the addition of appropriate excipients, into tablets, dragée cores or capsules. It is also possible for them to be incorporated into plastics carriers that allow the active ingredients to diffuse or be released in measured amounts.
- Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and binders, such as starch pastes using for example corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, and/or carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate.
- fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol
- cellulose preparations and/or calcium phosphates for example tricalcium phosphate or calcium hydrogen phosphate
- Excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
- Dragée cores are provided with suitable, optionally enteric, coatings, there being used, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as ethylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
- Capsules are dry-filled capsules made of gelatin and soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
- the dry-filled capsules may comprise the active ingredient in the form of granules, for example with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and if desired with stabilizers.
- the active ingredient is dissolved or suspended in suitable oily excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols, it being possible also for stabilizers and/or antibacterial agents to be added.
- suitable oily excipients such as fatty oils, paraffin oil or liquid polyethylene glycols, it being possible also for stabilizers and/or antibacterial agents to be added.
- Dyes or pigments may be added to the tablets or dragée coatings or the capsule casings, for example for identification purposes or to indicate different doses of active
- Tablet cores can be provided with suitable, optionally enteric, coatings through the use of, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations.
- suitable, optionally enteric, coatings through the use of, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations.
- compositions for oral administration also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticizer.
- the hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, binders, and/or glidants, and optionally stabilizers.
- the active ingredient is dissolved or suspended in suitable liquid excipients, to which stabilizers and detergents may also be added.
- compositions suitable for rectal administration are, for example, suppositories that consist of a combination of the active ingredient and a suppository base.
- aqueous solutions of an active ingredient in water-soluble form for example of a water-soluble salt, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers, are especially suitable.
- the active ingredient optionally together with excipients, can also be in the form of a lyophilizate and can be made into a solution before parenteral administration by the addition of suitable solvents.
- Solutions which are used, for example, for parenteral administration, can also be employed as infusion solutions.
- the present technology provides a method of treatment comprising administering a therapeutically effective amount of the compound or the composition of the present technology to a subject suffering from a disease, the pathology and/or symptoms of which disease can be prevented, inhibited or ameliorated by inhibition of the activity of a protein kinase.
- the protein kinase is a tyrosine kinase.
- the protein kinase is FGFR1, FGFR2, FGFR3, or FGFR4.
- the compound of the technology can be administered as such or especially in the form of pharmaceutical compositions, prophylactically or therapeutically, in an amount effective against the said diseases, to a subject, for example a human, requiring such treatment.
- a subject for example a human
- the daily dose administered is from approximately 0.05 g to approximately 5 g, or from approximately 0.25 g to approximately 1.5 g, of a compound of the present technology.
- the present technology relates to the use of the compound, or a pharmaceutically acceptable salt thereof, of the present technology, as such or in the form of a pharmaceutical composition with at least one pharmaceutically acceptable carrier for the therapeutic and also prophylactic management of one or more of the diseases mentioned above, for example, and without limitation, a disease which responds to an inhibition of a protein kinase, especially a neoplastic or tumor disease, especially solid tumor, more especially those cancers in which FGFR kinases are implicated including breast cancer, gastric cancer, lung cancer, cancer of the prostate, bladder cancer and endometrial cancer.
- Further cancer includes kidneys, liver, adrenal glands, stomach, ovaries, colon, rectum, pancreas, vagina or thyroid, sarcoma, glioblastomas and numerous tumours of the neck and head, as well as leukemias and multiple myeloma.
- the present invention related to the use of the compound of the present invention for the treatment of a warm-blooded animal having a disorder mediated by the fibroblast growth factor receptor (FGFR), in particular 8p11 myeloproliferative syndrome (EMS), pituitary tumors, retinoblastoma, synovial sarcoma, chronic obstructive pulmonary disease (COPD), seborrheic keratosis, obesity, diabetes and related disorders, autosomal dominant hypophosphatemic Rickets (ADHR), X-chromosome linked hypophosphatemic rickets (XLH), tumor-induced osteomalacia (TIO) and fibrous dysplasia of the bone (FD) as well as to a method of promoting localized neochondrogenesis, as well as a method of treating hepatocellular carcinoma, lung cancer, especially pulmonary adenocarcinoma, oral squameous cell carcinoma or esophageal squameous cell
- FGFR
- the present technology also provides for a method of treating a protein kinase dependent disease, comprising administering to a subject, for example a human, one or more cytostatic or cytotoxic compounds, e.g., and without limitation, imatinib (GLIVEC), in combination with the compound of the technology, whether at the same time, or a separate time.
- a subject for example a human
- one or more cytostatic or cytotoxic compounds e.g., and without limitation, imatinib (GLIVEC)
- imatinib e.g., imatinib
- antiproliferative agents include, but are not limited to aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, alkylating agents, histone deacetylase inhibitors, farnesyl transferase inhibitors, COX-2 inhibitors, MMP inhibitors, mTOR inhibitors, antineoplastic antimetabolites, platin compounds, compounds decreasing the protein kinase activity and further anti-angiogenic compounds, gonadorelin agonists, anti-androgens, bengamides, bisphosphonates, antiproliferative antibodies and temozolomide (TEMODAL®).
- aromatase inhibitors include, but are not limited to aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, alkylating agents, histone deacetylase inhibitors, farnesyl transferase inhibitors, CO
- Metabolic stability or clearance is a factor in determining drug concentration in blood.
- CL hepatic clearance
- the metabolic stability of each of Compounds 1 and 2 were determined at a concentration of 1 ⁇ M in mouse, rat, dog, monkey and human hepatic microsomal preparations.
- the compound tested, microsomal protein, and co-factors were combined, in duplicate, and incubated under appropriate conditions. Aliquots were removed at 0, 10 and 30 min, centrifuged and the supernatants analyzed by LC/MS/MS. Based on the percentage of the test compound remaining relative to the 0 min time point, the in vitro elimination rate constant, in vitro half-life (t 1/2 ) and in vitro intrinsic clearance (CL int ) parameters were calculate which allow for predicting the CL h values. The results are tabulated below and demonstrate that Compound 1 has a higher metabolic stability than Compound 2.
- Caco-2 cells are a human colonic adenocarcinoma cell line used to demonstrate drug absorption, and the role of non-passive diffusion processes in drug transport. Caco-2 cells were seeded on PET (polyethylene terephthalate) filters in a 96 well format and cultured for 18-25 days to develop monolayers.
- Test compound solutions (10 ⁇ M in transport buffer) were added to either the apical (A) or basolateral (B) side of the Caco-2 cell monolayer to measure the membrane permeability from the A to B compartments [Papp(A-B)] or from the B to A compartments [Papp(B-A].
- the assay was carried out in HBSS (Hank's Balanced Salts) buffer, pH 7.4 (for both sides) for 120 min at 37° C. Samples were taken from apical or basolateral compartments at scheduled times (0 min and 120 min) and quantified by LC/MS/MS. The results are presented in Table 4.
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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EP09174619 | 2009-10-30 | ||
EP09174619.8 | 2009-10-30 | ||
PCT/EP2010/066435 WO2011051425A1 (en) | 2009-10-30 | 2010-10-29 | N-oxide of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/EP2010/066435 A-371-Of-International WO2011051425A1 (en) | 2009-10-30 | 2010-10-29 | N-oxide of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea |
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US14/477,949 Continuation US20140378468A1 (en) | 2009-10-30 | 2014-09-05 | N-Oxide of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1--1-methyl-urea |
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US20120220600A1 true US20120220600A1 (en) | 2012-08-30 |
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US13/504,258 Abandoned US20120220600A1 (en) | 2009-10-30 | 2010-10-29 | N-Oxide of 3-(2,6-dichloro-3,5-dimethoxy-phenyl) -1--1-methyl-urea |
US14/477,949 Abandoned US20140378468A1 (en) | 2009-10-30 | 2014-09-05 | N-Oxide of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1--1-methyl-urea |
US14/971,412 Abandoned US20160102062A1 (en) | 2009-10-30 | 2015-12-16 | N-Oxide of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1--1-methyl-urea |
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US14/971,412 Abandoned US20160102062A1 (en) | 2009-10-30 | 2015-12-16 | N-Oxide of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1--1-methyl-urea |
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EP (1) | EP2493864B1 (nl) |
KR (1) | KR20120101367A (nl) |
CN (1) | CN102596916B (nl) |
ES (1) | ES2524548T3 (nl) |
IN (1) | IN2012DN03180A (nl) |
WO (1) | WO2011051425A1 (nl) |
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US20090137804A1 (en) * | 2004-06-24 | 2009-05-28 | Qiang Ding | Compounds and Compositions as Protein Kinase Inhibitors |
US10463653B2 (en) | 2014-10-03 | 2019-11-05 | Novartis Ag | Use of ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors |
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AU2013241664B2 (en) * | 2012-03-30 | 2016-05-19 | Novartis Ag | FGFR inhibitor for use in the treatment of hypophosphatemic disorders |
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US9266892B2 (en) | 2012-12-19 | 2016-02-23 | Incyte Holdings Corporation | Fused pyrazoles as FGFR inhibitors |
AR094812A1 (es) | 2013-02-20 | 2015-08-26 | Eisai R&D Man Co Ltd | Derivado de piridina monocíclico como inhibidor del fgfr |
RS56924B9 (sr) | 2013-04-19 | 2019-09-30 | Incyte Holdings Corp | Biciklični heterocikli kao fgfr inhibitori |
SG11201602183QA (en) | 2013-10-25 | 2016-05-30 | Novartis Ag | Ring-fused bicyclic pyridyl derivatives as fgfr4 inhibitors |
CA2956270C (en) | 2014-08-18 | 2022-08-09 | Eisai R&D Management Co., Ltd. | Salt of monocyclic pyridine derivative and crystal thereof |
US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
MX2017010673A (es) | 2015-02-20 | 2018-03-21 | Incyte Corp | Heterociclos biciclicos como inhibidores de receptores del factor de crecimiento fibroblastico (fgfr). |
MA41551A (fr) | 2015-02-20 | 2017-12-26 | Incyte Corp | Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4 |
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KR20170129757A (ko) * | 2015-03-25 | 2017-11-27 | 노파르티스 아게 | Fgfr4 억제제로서의 포르밀화 n-헤테로시클릭 유도체 |
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US11591329B2 (en) | 2019-07-09 | 2023-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
MX2022004513A (es) | 2019-10-14 | 2022-07-19 | Incyte Corp | Heterociclos biciclicos como inhibidores de los receptores del factor de crecimiento de fibroblastos (fgfr). |
WO2021076728A1 (en) | 2019-10-16 | 2021-04-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
CR20220285A (es) | 2019-12-04 | 2022-10-27 | Incyte Corp | Derivados de un inhibidor de fgfr |
US11897891B2 (en) | 2019-12-04 | 2024-02-13 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
CN113185510B (zh) * | 2021-04-12 | 2022-05-13 | 南京海纳医药科技股份有限公司 | 一种阿伐曲泊帕杂质的制备方法 |
WO2022261160A1 (en) | 2021-06-09 | 2022-12-15 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006000420A1 (en) * | 2004-06-24 | 2006-01-05 | Novartis Ag | Pyrimidine urea derivatives as kinase inhibitors |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU770600B2 (en) * | 1999-10-07 | 2004-02-26 | Amgen, Inc. | Triazine kinase inhibitors |
MEP3808A (xx) * | 2005-12-21 | 2010-02-10 | Novartis Ag | Derivati pirimidinil aril uree kao fgf inhibitori |
-
2010
- 2010-10-29 KR KR1020127010832A patent/KR20120101367A/ko not_active Application Discontinuation
- 2010-10-29 CN CN201080048756.3A patent/CN102596916B/zh not_active Expired - Fee Related
- 2010-10-29 EP EP10771744.9A patent/EP2493864B1/en not_active Not-in-force
- 2010-10-29 US US13/504,258 patent/US20120220600A1/en not_active Abandoned
- 2010-10-29 ES ES10771744.9T patent/ES2524548T3/es active Active
- 2010-10-29 WO PCT/EP2010/066435 patent/WO2011051425A1/en active Application Filing
- 2010-10-29 IN IN3180DEN2012 patent/IN2012DN03180A/en unknown
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2014
- 2014-09-05 US US14/477,949 patent/US20140378468A1/en not_active Abandoned
-
2015
- 2015-12-16 US US14/971,412 patent/US20160102062A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006000420A1 (en) * | 2004-06-24 | 2006-01-05 | Novartis Ag | Pyrimidine urea derivatives as kinase inhibitors |
US8552002B2 (en) * | 2004-06-24 | 2013-10-08 | Novartis Ag | Compounds and compositions as protein kinase inhibitors |
Non-Patent Citations (5)
Title |
---|
Cerecetto et al. (Mini Reviews in Medicinal Chemistry (2001), vol. 1 (3); pp. 219-231) * |
Christopher et al.(Drug Metabolism and Disposition (2008), vol. 36 (7); pp. 1357-1364 * |
Ma et al. (Rapid Commun. Mass Spectrom. (May 2009), vol. 23(10); pp. 1446-1450 * |
Patterson, L.H. (Drug Metab Rev (2002) vol. 34(3); pp. 581-592) * |
Wilson et al. (British Journal of Cancer (1996) 74, (Suppl. XXVII) S43-S47), * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090137804A1 (en) * | 2004-06-24 | 2009-05-28 | Qiang Ding | Compounds and Compositions as Protein Kinase Inhibitors |
US8552002B2 (en) | 2004-06-24 | 2013-10-08 | Novartis Ag | Compounds and compositions as protein kinase inhibitors |
US10463653B2 (en) | 2014-10-03 | 2019-11-05 | Novartis Ag | Use of ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors |
US10507201B2 (en) | 2014-10-03 | 2019-12-17 | Novartis Ag | Use of ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors |
Also Published As
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EP2493864B1 (en) | 2014-10-01 |
US20160102062A1 (en) | 2016-04-14 |
KR20120101367A (ko) | 2012-09-13 |
ES2524548T3 (es) | 2014-12-10 |
WO2011051425A1 (en) | 2011-05-05 |
EP2493864A1 (en) | 2012-09-05 |
CN102596916B (zh) | 2015-06-17 |
US20140378468A1 (en) | 2014-12-25 |
CN102596916A (zh) | 2012-07-18 |
IN2012DN03180A (nl) | 2015-09-25 |
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